Symptom Assessment Scale Helps Clinicians Treat Anemia of Cancer

Cancer patients undergoing chemotherapy experience distressing symptoms which impair their quality of life. In many cases, symptoms are related not only to cancer and chemotherapy, but also to chemotherapy-induced anemia. Darbepoetin-alfa is a standard of care for stimulating production of red blood cells in anemic cancer patients, and has been shown to improve symptoms such as fatigue. To improve quality of life and to evaluate other related symptoms in patients with chemotherapy-induced anemia, the M.D. Anderson Symptom Inventory (MDASI) has been developed. The MDASI is a self-rating symptom assessment scale, but has not yet been tested in broad patient populations. Recently, the first large-scale study of the MDASI was undertaken to assess associations between hemoglobin (Hb) levels and self-perceived symptoms in patients undergoing darbepoetin-alfa treatments for chemotherapy-induced anemia.

This open-label, 26-week study was conducted at multiple medical institutions across the United States. Patients aged 18 years or older with chemotherapy-induced anemia (Hb less than or equal to 11.0g/dL) were eligible to enroll. Every 2 weeks, patients received subcutaneous injections of darbepoetin-alfa (200 ug) for up to 24 weeks. Dosage was adjusted accordingly for patients with insufficient or excessive changes in Hb levels. Patient’s Hb levels were measured before each dose, and a follow-up visit occurred 2 weeks after the final injection. Also, at each visit, patients used the MDASI to assess symptom severity and interference before learning their Hb level. The study’s primary endpoint was the change in MDASI scores in relation to changing Hb levels.

Initially, 2,422 patients were enrolled, and 1,276 completed the study. In terms of hematologic outcomes, darbepoetin-alfa administration increased mean Hb levels. Over 90% of patients reached target Hb levels (Hb greater than or equal to 11.0g/dL), and approximately 80% of patients were able to maintain Hb levels between 11 and 13g/dL. In turn, improved MDASI scores seemed to be associated with increased Hb levels. Patients who experienced an Hb increase of 2g/dL reported significant improvements in all anemia-related scores. In contrast, patients with little or no increase in Hb levels reported no changes in symptom improvement on the MDASI.

Because physicians have limited time to evaluate patients in the clinic, the MDASI is a tool designed to provide fast and reliable symptom assessment. This study has shown that by using the MDASI, patients can accurately report a variety of symptoms related to chemotherapy-induced anemia. Physicians and clinicians can utilize this information to avoid problems with data collection and to make better treatment decisions for patients. In this study, darbepoetin-alpha was associated with improvement in a majority of cancer and chemotherapy-related symptoms measured by the MDASI. The study suggests that anemia may be responsible for a majority of these symptoms, even those that were not ascribed to anemia in the past.

Please reference the source article:
Assessing symptom burden using the M. D. Anderson symptom inventory in patients with chemotherapy-induced anemia: results of a multicenter, open-label study (SURPASS) of patients treated with darbepoetin-alpha at a dose of 200 microg every 2 weeks. Gabrilove JL, Perez EA, Tomita DK, Rossi G, Cleeland CS. Cancer. 2007 Oct 1;110(7):1629-40.

NAAC Expert Commentary:
Cancer and chemotherapy are associated with a number of distressing symptoms. Some of these symptoms, such as fatigue, interference with daily activity, distress, depression, dyspnea, and memory loss appear related to anemia, which is a common complication of cancer. These symptoms are improved by the correction of anemia. Other symptoms, such as dry mouth, nausea, vomiting, and pain, do not have a clear relation to anemia. In this important study, Gabrilove et al, demonstrated that 14 common symptoms of cancer, including those unrelated to anemia, improve with the correction of anemia in cancer patients receiving chemotherapy. This study is important because it reveals the pervasive effects of anemia on the complications of cancer and of chemotherapy.

However, before recommending that all cancer patients on chemotherapy receive treatment with ESA, more information is needed. First, it is important to document the long-term safety of these compounds, which has been challenged by recent studies. Second, it would be important to establish whether this symptomatic improvement is clinically significant, in addition to statistical significance. In other words, does symptomatic improvement translate to more meaningful and active life expectancy? Hopefully this important study will stimulate future trials to address this problem.

Partial Trial Stabilizing Hemoglobin Levels in Cervical Cancer

Patients with advanced cervical cancer benefit from concurrent cisplatin-containing chemotherapy with pelvic irradiation. However, unsatisfactory treatment results have led recent efforts to explore specific molecular or clinical features that are expressed by these tumors. In particular, anemia and tumor hypoxia are two relevant targets. Previous studies have indicated that anemia predicts for poorer local control and overall survival for cervical cancer patients. Commonly, clinicians have corrected anemia in these patients by administering blood transfusions. However, a recent study investigated whether raising and maintaining hemoglobin (Hb) levels above 12.0g/dL using recombinant human erythropoietin (rHuEPO) would improve progression-free survival and overall survival.

Patients with untreated, advanced cervical cancer with a presenting Hb level below 14.0g/dL were eligible for this study. Patients randomly received rHuEPO to raise and maintain Hb levels at or above 13.0g/dL. In control patients, transfusions were given if Hb levels fell below 10.0g/dL. The study’s primary endpoints were defined as progression survival, overall survival, and local control. In addition, platinum-DNA adducts in buccal cells were evaluated as potential prognostic markers of this patient population. High levels of DNA adducts could indicate less efficient DNA repair, and thus, could help predict tumors sensitive to cell cycle arrest or apoptosis.

Due to concerns for thromboembolic event (TE) with rHuEPO treatment, this study was closed after less than 25% of the planned accrual. In the rHuEPO treatment group, 19% (11 of 57) of patients experienced TE, compared to 7% (4 of 52) of patients in the control group. However, the study was unable to determine if occurrences of TE were related to rHuEPO treatment. Also, from data available for 53 patients, the study was unable to find a relationship between pre- and post-cycle platinum-DNA adduct levels.

Although this study was unable to determine the impact of raising and maintaining Hb levels during cervical cancer treatment, anemia and tumor hypoxia remain relevant therapeutic targets. Determining causal links between cervical cancer, anemia, and tumor hypoxia could lead to enhanced radio-sensitivity and chemo-sensitivity of cervical tumors. While the use of rHuEPO may increase the risk of TE, it is well recognized that TE occurs frequently without erythrocyte-stimulating agents. The authors concluded further studies are needed to determine if an increased rate of TE is an acceptable risk if rHuEPO treatment strategy leads to improved survival.

Please reference the source article:
Phase III trial to evaluate the efficacy of maintaining hemoglobin levels above 120 g/dL with erythropoietin vs above 100 g/dL without erythropoietin in anemic patients receiving concurrent radiation and cisplatin for cervical cancer. Thomas G, Ali S, Hoebers FJ, Darcy KM, Rodgers WH, Patel M, Abulafia O, Lucci JA 3rd, Begg AC. Gynecol Oncol. 2007 Nov 23.

NAAC Expert Commentary:
This paper presents an overview of the relationship between hemoglobin levels, tissue hypoxia, tumor angiogenesis and combined cisplatinum/radiation therapy in advanced cervical cancer. The authors correctly point out that although a low hemoglobin level before or during therapy is a poor prognostic indicator, a cause and effect relationship has not been established. They cite literature which suggests proportionately better outcomes for patients with hemoglobin levels maintained at 12g/dL compared to10g/dL during the course of therapy, which has led clinicians to transfuse anemic patients to those higher levels.

They undertook this study to ascertain whether using recombinant erythropoietin (rHuEPO) to maintain hemoglobin levels above 12g/dL would lead to improved outcomes for advanced cervical cancer patients compared to a control group whose hemoglobin levels would be maintained above 10g/dL through the use of red cell transfusion. Unfortunately, the study was terminated long before an adequate sample size could be obtained because of the occurrence of a large number of thromboembolic events particularly in the group receiving erythropoietin. As a result, the study did not produce any significant conclusions, but there are lessons to learn from its design and the discussion.

Despite randomizing patients to two groups, one receiving erythropoietin and the other not, more than half in each group were transfused, potentially confounding the outcomes for the rHuEPO group. There may have been a disproportionate number of patients with more advanced disease and larger tumors in the rHuEPO group, predisposing them to poorer outcome. (This selection bias might have been eliminated with larger numbers). There was no assessment of iron stores prior to initiating erythropoietin therapy, which might have inhibited efficacy of the treatment.

Finally, the study was ended because of a large number of thromboembolic events primarily in the rHuEPO group. The difference between the groups was not statistically significant, and the authors discuss the generally increased risk of these complications in advanced cervical cancer patients. But in context of other recent reports of a possible association of thromboembolic occurrences with the use of this agent, the study was discontinued.

The real contribution of this paper is that it reminds us that anemia, though a poor prognostic factor in many cancers, may or may not be the cause. The use of transfusion with its immunomodulating effects in these patients may introduce confounding variables. It is important to study the effects of correcting anemia in a more physiological way to answer this question.

Clinical Efficacy and Economic Burden of Iron Chelation Therapy

Treatment for hemoglobin disorders such as thalassemia and sickle cell disease require patients to undergo chronic blood transfusions, often resulting in iron overload which leads to organ damage. Because the body cannot naturally excrete iron, iron chelation therapy (ICT) is used to remove the excess iron. Although Deferoxamine has been the standard chelating agent to treat iron overload, compliance to ICT is suboptimal due to the burdensome, 8-12 hour transfusions required 5-7 times per week. Recently, a naturalistic study cohort was conducted to assess the clinical effectiveness and economic burden of ICT based on serum ferritin levels, quality of life (QOL) reports, compliance, and costs.

The study, which was conducted at four medical facilities in the United States, included 49 male and female patients 6 years of age or older who had been undergoing ICT for at least 3 months at the time of enrollment. During the initial site visit, sociodemographic, compliance, treatment satisfaction, QOL reports, and serum ferritin data were collected. In addition to patient data, Payne et al conducted a literature review to identify prior studies reporting costs of ICT.

In general, serum ferritin levels obtained from patients were unacceptably high (greater than 2500 mg/mL) and remained stable during ICT. Medical charts also indicated patient comorbidities related to transfusion iron overload which included osteoporosis (40%), hepatitis C (38%), delayed puberty (26%), hormone problems (24%), stunted growth (18%), cardiac complications (14%), complications of the spleen (14%), hypothyroidism (12%), and diabetes (10%). In terms of QOL, overall patient self-reports indicated a significant impairment, with 55% of patients reporting at least one adverse event in the 30 days before the study, including site soreness, site irritation, ringing in the ears, and temporary hearing loss. Importantly, 60% of patients reported missing at least one dose and 46% reported missing two doses in the week previous to the initial visit. Additionally, a review of current literature identified a single publication in which the estimated lifetime costs of DFO alone averaged $63,000 per patient. This total did not include homecare or other ancillary costs.

These results indicate that the clinical and economic burdens of ICT are significant. Patient reported compliance was poor, and was directly associated with high ferritin levels. Poor compliance is likely due to the burdensome nature of ICT, as well as the many adverse events patients experience. However, due to the small sample size and limited number of study sites, these results may not be generalizable across all ICT patient populations. Future studies are needed to assess the significance of other clinical markers besides serum ferritin. Also, because only a small number of studies reported the costs of ICT, an interpretation of comprehensive costs is difficult without further examination.

Please reference the source article:
Clinical and economic burden of infused iron chelation therapy in the United States. Payne KA, Desrosiers MP, Caro JJ, Baladi JF, Lordan N, Proskorovsky I, Ishak K, Rofail D. Drugs 67(2): 175-94. Transfusion. 2007 Oct;47(10):1820-9.

NAAC Expert Commentary:
One of the most devastating complications of chronic transfusion therapy is iron overload. Under normal physiological conditions, iron homeostasis is tightly regulated, such that the daily amount of iron absorbed from the diet (about 1mg in men and 1.5 mg in woman) balances the same amount of iron lost per day via shedding of skin, the GI track, and menstrual blood loss. When a large excess of iron, approximately 200 mg per blood unit, enters the body from red cell transfusion therapy there is limited capacity to deal with this excess iron. It has been estimated that 10-30 transfusions may saturate the body’s iron storage system. When this occurs, iron accumulates in various organs, particularly the liver and heart. While the majority of iron accumulates in the liver, heart failure is the most common cause of death from iron overload. It is thus critical that patients in need of chronic transfusion therapy, such as thalassemia or sickle cell disease undergo iron chelation therapy (ICT).

In the paper by Payne et al, the clinical effectiveness and cost of Deferoxamine, the standard approach to ICT at this time, is examined in a small cohort of patients in their day to day activities (naturalistic study). Compared to a clinical trial, where everything is carefully controlled, a naturalistic study is more useful in assessing the effectiveness of a therapy in the real world. According to Payne et al the yearly cost of ICT is $34,460.00 for the initial treatment year and $30,004.00 for subsequent years. The efficacy of ICT, however, is rather poor with the serum ferritin remaining stable at approximately 2500 mg/mL, despite treatment. This result is due in part to the variable compliance with the chelation regimen. Poor compliance is related to the nearly daily treatment sessions necessary for up to 12 hours each, and associated various, generally localized side-effects. Better results in the ferritin levels are achieved when there is perfect compliance compared to those who miss one or more sessions per week. All in all, Payne et al speaks to the need of a more patient-friendly ICT regimen that will promote patient compliance and improve clinical impact.